Murine resistance to intraperitoneally (i.p.)-inoculated street rabies virus (SRV) has been shown to be dominant and genetically controlled by the concurrent presence of each of two segregating genes. Trace experiments for infectious SRV indicated that susceptibility differences among genetically dissimilar strains of mice were associated with restriction of viral replication within the central nervous system (CNS). Limitation of viral replication appeared to correlate with the antibody response. The importance of the immune response was reaffirmed with cyclophosphamide studies in that all resistant SJL/J mice died following immunosuppressive treatment. In contrast, cyclophosphamide-treated SJL/J mice and immunodeficient athymic mice were protected when reconstituted with immune serum starting at 72hr after SRV inoculation, a time in which virus was not detected in the peritoneal cavity, but was present in the spinal cord. Passively transferred unfractionated immune cells also protected athymic mice. Specific cell eliminations with cytotoxic antibody and complement indicated B cells, but not T cells, were essential for protection. Additional studies showed that neutralizing antibody in the cerebrospinal fluid was unimportant in the resistance of mouse strains which remained CNS clinically asymptomatic. Furthermore, the CNS of mice inoculated i.p. 5 days previously with SRV was resistant to either intracerebral or intranasal rabies virus challenge. Survival of these mice correlated with the detection of neutralizing antibody in serum. A focal immunofluorescent assay (FIA) on live cells has been developed for quantification and biological cloning of street and laboratory-adapted strains of rabies viruses. Monoclonal antibodies, in conjunction with mutagenic agents and the FIA assays, are being utilized for selection of avirulent and virulent isolates of rabies viruses. Preliminary studies indicate that only monoclonal antibodies with neutralizing activity inhibit replication of rabies virus in vitro, and protect cyclophosphamide immunosuppressed SJL/J mice.